title: Synthesis and biological evaluation of novel pyrido[2,3-b]pyrazines inhibiting both erlotinib-sensitive and erlotinib-resistant cell lines.
abstract: A series of novel pyrido[2,3-b]pyrazines were synthesized as potential antitumor agents for erlotinib-resistant tumors. Known signal inhibitor compounds from our Nested Chemical Library were tested in phenotypic assays on erlotinib-sensitive PC9 and erlotinib-resistant PC9-ER cell lines to find a compound class to be active on erlotinib resistant cell lines. Based on the screening data, novel pyrido[2,3-b]pyrazines were designed and synthesized. The effect of the substituent position of the heteroaromatic moiety in position 7 and the importance of unsubstituted position 2 of the pyridopyrazine core were explored. Compound 7n had an IC50 value of 0.09 μM for the inhibition of PC9 and 0.15 μM for the inhibition of PC9-ER. We found that some lead compounds of these structures overcome erlotinib-resistance which might become promising drug candidates to fight against NSCLC with EGFR T790M mutation. The signaling network(s) involved in the mechanism(s) of action of these novel compounds in overcoming erlotinib resistance remain to be elucidated.
authors.affiliation: Vichem Chemie Research Ltd., Herman Ottó u. 15., H-1022 Budapest, Hungary; Rational Drug Design Laboratory CRC, Semmelweis University, POB 131, H-1367 Budapest 5., Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Kékesi
authors.forename: Anna
authors.initials: A
authors.lastname: Sipos
authors.forename: Gábor
authors.initials: G
authors.lastname: Németh
authors.forename: János
authors.initials: J
authors.lastname: Pató
authors.forename: Nóra
authors.initials: N
authors.lastname: Breza
authors.forename: Ferenc
authors.initials: F
authors.lastname: Baska
authors.forename: László
authors.initials: L
authors.lastname: Őrfi
authors.forename: György
authors.initials: G
authors.lastname: Kéri
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride
keywords: Erlotinib resistance; Inhibitor; PC9; PC9-ER; Phenotypic screen; Pyrido[2,3-b]pyrazine